The primary goal of this proposal is to learn more about early events in epithelial carcinogenesis and the factors that are related to progression of premalignant proliferations to overt malignancy. The experimental model to be used is two-stage carcinogen-induced skin tumors in female mice with X- chromosome linked phosphoglycerate kinase (PGK) cell markers. Specifically, we will attempt to answer the following questions about mouse skin tumor development in the hope of further understanding human tumorigenesis: Do spontaneously-occurring mouse skin papillomas progress sequentially to carcinomas? Can promotor-dependent papillomas induced by very low doses of DMBA initiation and a standard dose of TPA promotion be advanced to promoter-independent papillomas or carcinomas by increasing the dose of TPA or by increasing the length of promotion? In mice initiated with high doses of DMBA, does a decrease in the dose of TPA, a decrease in the length of promotion or substitution of a weak promoter for TPA during the first course of promotion result in the induction of papillomas which are primarily promoter-independent? Do papillomas induced by initiation with weak carcinogens and TPA promotion change their clonal phenotype during progression as occurs in those induced by DMBA and TPA? What is the mechanism of regression of promoter-dependent papillomas? These experiments should permit further development of a model of carcinogenesis that may be useful in investigation of molecular mechanisms of oncogenesis and could suggest a better means of approaching study of epithelial carcinogenesis in humans.